Published online before print April 5, 2004, doi: 10.1161/01.CIR.0000121732.85572.6F
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(Circulation. 2004;109:1769-1775.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Enhanced Inhibition of Neointimal Hyperplasia by Genetically Engineered Endothelial Progenitor Cells
From the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (D.K., L.G.M., A.A.M., L.Z., M.L.-I., M.A.P., C.C.L., R.E.P., V.J.D.), and the Department of Physiology, Queen’s University, Kingston, Ontario, Canada (L.G.M.). Dr Kong is currently at the College of Science, Nankai University, People’s Republic of China.
Correspondence to Victor J. Dzau, MD, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail vdzau{at}partners.org
Received August 12, 2003; revision received December 3, 2003; accepted December 5, 2003.
Background— Circulating endothelial progenitor cells (EPCs) have been reported previously. In this study, we examined the hypothesis that overexpression of vasculoprotective gene endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) in EPCs enhances their ability to inhibit neointimal hyperplasia.
Methods and Results— EPCs were isolated from rabbit peripheral blood, expanded in culture, and transduced with pseudotyped retroviral vectors expressing human eNOS (eNOS-EPCs), HO-1 (HO-1-EPCs), or green fluorescent protein (GFP-EPCs). Transduction efficiency of EPCs ex vivo was >90%. Four groups of rabbits (n=5 to 6 per group) were subjected to balloon angioplasty of the common carotid artery. Immediately after injury, 
5x106 autologous eNOS-EPCs or HO-1-EPCs were transplanted into the injured vessel. Control animals received an equivalent number of GFP-EPCs or Ringer’s saline. Two weeks after transplantation, eNOS and HO-1 transgene transcripts and proteins were detected in the transduced rabbit vessels. Endothelialization was enhanced in the EPC-transplanted vessels independently of gene transfer. Neointimal thickening was significantly reduced in the GFP-EPC-treated vessels relative to the saline control. Neointima size was further reduced in vessels treated with eNOS-EPCs. Surprisingly, no additional reduction was seen in vessels treated with HO-1-EPCs relative to GFP-EPCs. Thrombosis occurred in 50% of the saline-treated vessels but was virtually absent in all EPC-transplanted vessels.
Conclusions— We conclude that transplantation of autologous EPCs overexpressing eNOS in injured vessels enhances the vasculoprotective properties of the reconstituted endothelium, leading to inhibition of neointimal hyperplasia. This cell-based gene therapy strategy may be useful in treatment of vascular disease.
Key Words: endothelium • cells • hyperplasia • gene therapy
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